This invention relates to the nickel catalyzed formation of novel unsymmetrical tertiary amines. More particularly, the invention relates to
(4-halo-phenyl)-phenyl-m-tolyl-aminesxe2x80x83xe2x80x83(I)
which may be converted to
N4,N4xe2x80x2-diphenyl-N4,N4-di-m-tolyl-biphenyl-4,4xe2x80x2diaminexe2x80x83xe2x80x83(II)
by nickel catalyzed coupling.
It is known to produce (II) by palladium catalyzed amination using m-methyldiphenylamine, 4,4xe2x80x2-dibromobiphenyl and tri-tert-butyl phosphine. See Yamamoto, T., et al., Tetrahedron Letters (1998) 39:2367-2370. It is also known to produce (II) by reaction of m-methyldiphenyl amine with 4,4xe2x80x2-diiodobiphenyl under copper powder in potassium hydroxide or other bases in high boiling solvents at 150-200xc2x0 C. See, e.g., U.S. Pat. No. 4,764,625. 1,10-phenanthroline has been used to ligate copper and the use of Cu(I) salts has been reported to reduce the temperature of this reaction to 125xc2x0 C. See Goodbrand, J. Org. Chem. (1999) 64:4290 and U.S. Pat. Nos. 5,654,482; 5,648,539; 5,648,542; 5,705,697; 5,723,669 and 5,723,671. Coupling of chlorobenzene to afford biphenyl and 4-chloroaniline to afford 4,4xe2x80x2-diaminobiphenyl using NiCl2, triphenylphosphine, zinc and DMF with and without 2,2xe2x80x2 bipyridyl is described in J. Org. Chem. (1986) 51:2367-2370. U.S. Pat. No. 4,263,466 describes a method for coupling aryl chlorides in which a nickel catalyst is generated in situ from nickel salts and excess reducing agents.
In general, a problem exists in that prior art procedures for producing (II) and similar compounds entail the use of biphenyl starting material including expensive dihalobiphenyls and harsh high temperature conditions.
A need exists for a more cost effective method for producing such compounds.
There is a particular need for a mild, low temperature nickel catalyzed synthesis of an intermediate which may be converted to compounds typified by (II).
Pursuant to this invention, the biphenyl moiety of compounds such as (II) is assembled after the amine moieties are in place. A novel intermediate (I) is synthesized. The intermediate is then coupled in a mild nickel catalyzed reaction. A novel intermediate, e.g., unsymmetrical, triarylamine (4-halo-phenyl)phenyl-m-tolyl amine (I) is first synthesized from cheap building blocks, typically m-toluidine, bromobenzene, and 1,4 bromo-chlorobenzene to yield triaryl amine chloride (I). The synthesis is accomplished via two, sequential palladium catalyzed aminations in one pot. The compound (I) may be crystallized in good yield, e.g., above 80% yield, and high purity, e.g., 95% purity. (II) is produced by nickel catalyzed coupling of (I).
Synthesis of (I) (4-Chloro-Phenyl-M-Tolyl Amines)
In the first step, the pot is charged under nitrogen with palladium acetate, tri-tert-butyl phosphine and dry deoxygenated toluene. A first reaction mixture of a red color results. Bromobenzene, sodium t-butoxide and m-toluidine are added sequentially under nitrogen. The reaction is heated with stirring under reflux for a time sufficient, e.g., 1 to 2.5 hours, to produce a reaction mixture containing 95-97% of m-methyl diphenyl amine. 1,4-bromo chlorobenzene and sodium t-butoxide are then added, and the reaction is stirred to reflect overnight to afford (I). The reaction is illustrated by Equation 1: 
In Equation 1, m-toluidine may be replaced by an compound of the formula: 
in which R is an ortho, meta, or para C1 to C10 alkyl substituent, 
may be replaced by any compound of the formula: 
in which X is any halogen or triflate.